A team led by scientists at The Scripps Research Institute has developed a potential new treatment for heart attacks. The therapy inhibits fluid leakage from cardiac blood vessels following a heart attack and thereby significantly prevents long-term heart damage and improves survival.

"Immediately following a heart attack, blood vessels near the site of injury become leaky, causing fluid accumulation in the healthy area of the heart surrounding the injured site," says Immunology Professor David A. Cheresh, Ph.D., who led the research with postdoctoral fellow Sara Weis, Ph.D at The Scripps Research Institute. This permeability response is devastating to normal heart tissue.

"Until now," continues Cheresh, "nobody has realized the extent to which this leak response damages heart tissue and causes long-term tissue injury. We discovered a way to block this process and thus save heart tissue from irreversible damage."

Using laboratory models that are designed to mimic the pathology of heart attacks in humans, Cheresh, Weis, and their colleagues found that a single dose of a compound designed to block this fluid leakage (which is called edema) can, even if given as late as six hours after the event, drastically reduce tissue injury and increase long-term survival following a heart attack.

A biopharmaceutical company, TargeGen Inc. in San Diego, is finalizing preclinical studies to translate these initial research findings into practical human therapies. Using extensive preclinical models that mirror human heart attacks, TargeGen scientists report that 40 to 60 percent reductions in infarct (tissue injury) size with a small molecule drug that inhibits vascular leak and edema. Based on the encouraging preclinical efficacy and safety studies, TargeGen plans to initiate a combined Phase I/II human clinical trial in the second half of 2004 for patients undergoing an acute heart attack.

In addition to Cheresh and Weis, the team included scientists from St. Elizabeth's Medical Center at Tufts University School of Medicine in Boston, Massachusetts; the Department of Radiology at Beth Israel Deaconess Medical Center in Boston; and the private company TargeGen, Inc. of San Diego, California.

Public Health Enemy Number One

According to the National Heart, Lung, and Blood Institute, about 12.6 million Americans suffer from coronary heart disease, the most common form of heart disease. This disease often leads to an acute myocardial infarction, the technical term for a heart attack. Some 1.1 million Americans suffer heart attacks each year, and approximately 515,000 of these attacks are fatal, making coronary heart disease the number one cause of death in the United States today.

Currently, the main treatments for heart attacks address the initial thrombus or blockage to the artery in order to restore blood flow to the heart. Doctors use thrombolytic "clot busting" drugs to dissolve the blockage chemically, or angioplasty--tiny balloon catheters often followed by a wire mesh stent--to mechanically prevent the artery from collapsing.

However, because the blockage starves the heart tissue of oxygen, says Cheresh, the tissue damage that occurs following a heart attack may continue to worsen in the hours following the attack, even after the clot is gone. The damage occurs because when the heart is starved of oxygen--a situation called ischemia--a whole cascade of events occurs, including edema (the leaking of blood vessels).

Edema causes fluid to accumulate in the heart tissue, which leads to rapid cell death in the local area where the fluid accumulates. It also leads to further loss of heart tissue through inflammatory reactions in the several hours following a heart attack. Over the long term, this edema-induced cell death leads to fibrosis, the formation of scar tissue which replaces dead heart tissue. Heart attack survivors often have weakened hearts because this scar tissue cannot function properly. These patients often require additional procedures, such as the insertion of pacemakers or heart transplants.

For the first time, a possible treatment for this secondary damage has been proposed by Cheresh, Weis, and their colleagues--the use of a class of compounds known as Src kinase inhibitors.

In the latest issue of the Journal of Clinical Investigation, the team reports a dramatic effect of using Src kinase inhibitors to stop the edema-induced damage following a heart attack, thereby reducing heart tissue injury and increasing survival.

Cell Adhesion and the Sequence of Events Following the Heart Attack

This possible treatment strategy stems from several years of basic research conducted by Cheresh and his collaborators into an area of biology known as cell adhesion.

Cell adhesion is a topic of major importance because it is the basis for how groups of cells form and define functionally distinct tissues and organs in the body. Blood vessels are lined by what are known as endothelial cells, which adhere to one another and line the body's blood vessels like bricks lining a subterranean tunnel.

Through the work of Cheresh and other basic science researchers over the past decades, a number of the adhesion molecules that hold these endothelial cells together and the signaling molecules that induce them to let go of one another during events like edema have been identified.

A heart attack occurs when a blood vessel in the heart becomes blocked. This leads to oxygen deprivation, and that rapidly induces the production of vascular endothelial cell growth factor (VEGF), which is known to promote new blood vessel growth. However, VEGF also produces the unwanted side effect of causing vascular permeability, and Cheresh and his colleagues wanted to develop a strategy to block blood vessel leak without blocking the beneficial vascular growth-promoting effects of VEGF. This was accomplished with a Src kinase inhibitor.

Normally cadherins form mortar-like junctions between the endothelial cell bricks and maintain the integrity of blood vessel walls. But cadherins come apart rapidly when they are given the right stimulus--such as VEGF.

Just as removing mortar between bricks in a subterranean tunnel might cause the tunnel to become permeable to groundwater, blood vessels become leaky when the mortar that holds these endothelial cells together crumbles.

A few years ago, Cheresh and his colleagues discovered that mice born without the ability to make certain proteins belonging to the Src family have a deficiency in vascular permeability. These animals showed a high degree of resistance to the damaging effects of a heart attack. Src, it turns out, is necessary for breaking the cadherin junctions in response to VEGF. In fact, these mice lacking Src were protected against the edema that followed a heart attack.

This led Cheresh and his colleagues to speculate that treating normal mice with Src inhibitors might do the same thing. In their latest study, they demonstrate exactly that result. The cadherin junctions between cells lining the blood vessels in animals treated with Src inhibitors following a heart attack do not break down.

"Src inhibitors prevent the endothelial barrier breakdown, thereby preventing the edema in the heart. This early protection reduces the loss of cardiac tissue and thus the necessity for replacement by a functionally inadequate scar," Cheresh says.